Molecular biomedicine最新文献

{"title":"Curcumin analogue FLLL32 induces ferroptosis by targeting the STAT3-GPX4/SLC40A1 axis in colorectal cancer.","authors":"Tong Wu, Mengqiu Hao, Qiuye Luo, Sicheng Liu, Yaguang Zhang, Yang Zhang, Xuyang Yang, Junhong Han","doi":"10.1186/s43556-026-00575-5","DOIUrl":"https://doi.org/10.1186/s43556-026-00575-5","url":null,"abstract":"<p><p>FLLL32 is a curcumin analogue with reported anti-tumor activity, mainly through inhibition of signal transducer and activator of transcription 3 (STAT3) signaling and induction of apoptosis. However, whether FLLL32 regulates ferroptosis in colorectal cancer (CRC) and the underlying mechanism remain unclear. Here, using a patient-derived CRC organoid screening platform, we identified FLLL32 as a potent anti-CRC compound. FLLL32 suppressed CRC organoid growth, inhibited CRC cell proliferation and migration in vitro, and inhibited xenograft tumor growth in vivo. In parallel, FLLL32 induced ferroptosis-associated iron accumulation, reactive oxygen species (ROS) production, lipid peroxidation, mitochondrial morphological and functional abnormalities. The ferroptosis inhibitor Ferrostatin-1 markedly restored FLLL32-impaired cell viability and reduced ROS, whereas the apoptosis inhibitor Z-VAD-FMK showed weaker protection. These findings suggest that ferroptosis is a major contributor to FLLL32-induced cell death, although apoptotic features are also present. Mechanistically, FLLL32 interacted with STAT3, and Glu638 and Met726 contributed to the FLLL32-STAT3 interaction. FLLL32 also suppressed STAT3 Tyr705 phosphorylation and nuclear signaling, thereby disrupting pSTAT3-mediated transcriptional regulation of glutathione peroxidase 4 (GPX4) and solute carrier family 40 member 1 (SLC40A1), weakening lipid peroxide detoxification and cellular iron efflux, promoting intracellular iron accumulation, and enhancing ferroptosis in CRC cells. These findings define a STAT3-GPX4/SLC40A1-dependent mechanism underlying the anti-CRC activity of FLLL32 and support further investigation of STAT3-associated ferroptosis regulation as a potential therapeutic vulnerability in CRC.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149229165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autism: epidemiology, genetics, molecular mechanisms, clinical features, diagnosis, and management.","authors":"Ruonan Fan, Yilin Wang, Tingting Miao","doi":"10.1186/s43556-026-00613-2","DOIUrl":"https://doi.org/10.1186/s43556-026-00613-2","url":null,"abstract":"<p><p>Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition characterized by persistent deficits in social communication and restricted, repetitive behaviors. Global prevalence has risen steadily, yet reported rates vary markedly across regions and populations. These discrepancies reflect inequities in diagnostic access and screening capacity rather than true differences in incidence. This review integrates recent advances across the full ASD research spectrum. We first examine global epidemiological patterns and demographic disparities. We then dissect the genetic architecture of ASD, including rare and common variants, copy number variations, and gene-environment interactions that disrupt prenatal and early postnatal brain development. At the molecular level, diverse risk factors converge on shared neurodevelopmental mechanisms. These include synaptic dysfunction, dysregulated signaling through mTOR, Ras-ERK-MAPK, Wnt and Notch pathways, impaired neurogenesis, chronic neuroimmune inflammation, and excitatory-inhibitory imbalance. We also discuss how these mechanisms manifest in core clinical features, including social deficits, repetitive behaviors, and sensory abnormalities. We summarize current diagnostic standards and their limitations. Cross-species animal models, from Drosophila to non-human primates, are evaluated for their essential roles in mechanistic validation and therapeutic screening. Finally, we assess clinical management strategies, ranging from behavioral and educational interventions to pharmacological and supportive services. By tracing a continuous path from risk factors at the population level through molecular pathophysiology to interventions guided by mechanism, this review offers an integrative synthesis that connects basic discovery to clinical translation. We further discuss how multi-omics and artificial intelligence may advance precise diagnosis rooted in mechanism and personalized treatment.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149229142","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lysine-specific demethylase 1 (LSD1) regulates macrophage plasticity and immune checkpoint expression in colorectal liver metastases.","authors":"Candela Cives-Losada, Cristiana Soldani, Michela Anna Polidoro, Barbara Franceschini, Flavio Milana, Aurora Gazzillo, Antonella Cammarota, Chiara Camisaschi, Francesca Clemente, Achille Anselmo, Luca Di Tommaso, Guido Torzilli, Domenico Mavilio, Ana Lleo, Matteo Donadon","doi":"10.1186/s43556-026-00602-5","DOIUrl":"https://doi.org/10.1186/s43556-026-00602-5","url":null,"abstract":"<p><p>Colorectal liver metastases (CRLM) are a major cause of mortality in colorectal cancer and are characterised by a profoundly immunosuppressive tumour microenvironment in which tumour-associated macrophages (TAMs) play a central role. However, the molecular mechanisms driving TAM plasticity and maintenance remain poorly understood. Here, we investigated macrophage heterogeneity in CRLM and examined the contribution of the epigenetic regulator lysine-specific demethylase 1 (LSD1) to TAM polarisation. Analysis of patient-derived specimens by flow cytometry, immunohistochemistry and transcriptional profiling identified a population of large TAMs (L-TAMs) enriched in the peritumoral niche that displayed an immunosuppressive, M2-like phenotype and was associated with poor clinical outcome. In contrast, smaller TAMs (S-TAMs) exhibited a more inflammatory transcriptional programme, including increased IL1β expression. Tumour-conditioned media reproduced these distinct macrophage phenotypes in vitro, indicating that tumour-derived factors actively shape TAM identity. Pharmacological inhibition of LSD1 using baicalin or INCB059872 reduced the expression of CD206 and the immune checkpoint molecule PD-L1, consistent with macrophage reprogramming away from a tumour-promoting state. Collectively, these findings identify LSD1 as an epigenetic regulator of macrophage plasticity in CRLM, implicated in the maintenance of immunosuppressive TAM phenotypes, and potentially able to induce phenotypic reversion. Our findings identify LSD1 as a regulator of TAM phenotype and support further investigation of LSD1 targeting as a strategy to remodel the metastatic tumour microenvironment and potentially enhance anti-tumour immunity.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149229081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage interferon regulatory factor 7 aggravates the progression of metabolic dysfunction-associated steatohepatitis.","authors":"Xuhao Ni, Qingfa Bu, Yuan Liang, Bozhou Pan, Jian Wang, Qingxiang Xu, Lei Liu, Qi Wang","doi":"10.1186/s43556-026-00601-6","DOIUrl":"https://doi.org/10.1186/s43556-026-00601-6","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatohepatitis (MASH) represents a growing clinical burden with increasing prevalence and lacking approved pharmacological therapies. Interferon regulatory factor 7 (IRF7) is a central mediator of type I interferon-dependent immune responses, yet the precise mechanisms by which macrophage-expressed IRF7 shapes inflammatory and metabolic events during MASH pathogenesis remain incompletely defined. This study aimed to dissect the functional role of IRF7 in MASH development. We assessed IRF7 expression in human and mouse liver specimens, and utilized myeloid-specific Irf7-deficient mice fed with high-fat high-cholesterol diet (HFHCD) or methionine-choline-deficient diet (MCD) to recapitulate MASH pathology. IRF7 was significantly elevated in MASH-affected livers, and myeloid-specific Irf7 deletion markedly mitigated MASH progression. Mechanistically, loss of IRF7 blunted IFN-α and IFN-β production, suppressing macrophage-derived type I interferon-dependent immune cascades. IRF7 directly bound to the promoters of pro-inflammatory Tnfa and Il1b to boost their transcription, and interacted with SMAD3 to activate Tgfb1 transcription. The E3 ubiquitin ligase HUWE1 mediated IRF7 monoubiquitination to enhance its nuclear translocation, driving transcription of pro-inflammatory and pro-fibrotic genes. This molecular cascade aggravated hepatic steatosis and triggered hepatic stellate cell (HSC) activation, accelerating MASH deterioration. Pharmacological IRF7 inhibition effectively counteracted these pathological alterations. Collectively, myeloid IRF7 fuels MASH progression by amplifying macrophage-mediated liver inflammation, suggesting IRF7 as a promising therapeutic target against MASH.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149225446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Synthetic Notch CD123 and CLL1 chimeric antigen receptor T-cells (CAR-T) target acute myeloid leukemia and reduce off-tumor effects associated with CLL1 CAR-T cells.","authors":"Rui Zhang, Na Chen, Mengnan Li, Qingxi Liu, Mingfeng Zhao","doi":"10.1186/s43556-026-00598-y","DOIUrl":"10.1186/s43556-026-00598-y","url":null,"abstract":"<p><p>Chimeric antigen receptor T-cell (CAR-T) therapy targeting the C-type lectin-like molecule-1 (CLL1) antigen has emerged as a promising therapeutic approach for acute myeloid leukemia (AML). However, its clinical translation is hindered by on-target, off-tumor toxicity, particularly severe neutropenia caused by CLL1 expression on normal neutrophils. To address this limitation, we constructed a synthetic Notch (SynNotch) dual-antigen AND-gated CAR-T system targeting CD123 and CLL1 to improve tumor specificity and reduce off-tumor toxicity. CD123 and CLL1 expression was first assessed in AML cell lines and primary AML blasts by flow cytometry. The in vitro cytotoxicity, serial killing activity, cytokine secretion, exhaustion-associated protein markers, and transcriptomic profiles of engineered CAR-T cells were then evaluated, and therapeutic efficacy and safety were further examined in AML xenograft models. SynNotch CD123 and CLL1 CAR-T cells showed stronger cytotoxic activity against AML blasts while exhibiting reduced activity toward normal neutrophils. In addition, these cells displayed lower expression of exhaustion-associated genes and markers, together with increased expression of genes related to naive/memory differentiation. In vivo, this CAR-T variant showed improved expansion, longer persistence, and stronger anti-leukemic activity, together with less severe neutropenia. Increased cytokine production in vitro indicated stronger T-cell activation but also suggested the need for careful evaluation of potential cytokine-related toxicity. These findings indicate that SynNotch dual-antigen-gated CAR-T cells may provide a more specific and potentially safer therapeutic strategy for relapsed/refractory AML.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675449/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208334","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Curcumin alleviates metabolic dysfunction-associated steatotic liver disease via gut microbiota-dependent epigenetic alterations.","authors":"Yong Zhu, Jinhu Ma, Danhong Wang, Mingzhu Cui, Jin Peng, Xuejin Lu, Xingyue Pei, Yi Wang, Jing Lv, Yuxuan Yan, Wenhao Ma, Mingtao Zhao, Shulei You, Jie Ma, Yunshu Tang, Yaling Zhu","doi":"10.1186/s43556-026-00606-1","DOIUrl":"10.1186/s43556-026-00606-1","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent, yet effective therapies remain limited. Curcumin (Cur), a polyphenol with well-documented metabolic benefits, shows therapeutic promise in MASLD, but its efficacy and underlying mechanisms remain incompletely understood. A meta-analysis of seven clinical studies indicated that Cur supplementation reduced serum aminotransferase levels, supporting its potential clinical benefit. In high-fat diet (HFD)-fed rats, Cur reduced hepatic lipid accumulation and metabolic dysfunction, whereas these effects were markedly weakened in antibiotic-induced pseudo-germ-free rats, indicating microbiota dependence. Fecal microbiota transplantation from Cur-treated donors transferred these metabolic and histological benefits to antibiotic-conditioned recipients. Fecal 16S rRNA sequencing identified Clostridium_sensu_stricto_1 (C. sensu) as a Cur-suppressed, pro-steatotic taxon, and targeted reconstitution of this taxon abolished Cur-mediated protection. Untargeted hepatic metabolomics and liquid chromatography-mass spectrometry identified kynurenine (KYN) as a C. sensu-derived metabolite and showed that Cur reduced hepatic KYN accumulation. Integrated H3K27ac ChIP-seq, bulk RNA-seq, and single-cell analyses pinpointed hepatocyte-enriched CEBPB as a key epigenetically regulated effector. Luciferase reporter assays, ChIP-qPCR, and gain- and loss-of-function experiments showed that KYN activated the aryl hydrocarbon receptor (AHR), increased H3K27ac enrichment at the Cebpb locus, and induced Cebpb transcription. CEBPB knockdown blocked KYN-induced PI3K-AKT activation and lipid accumulation, whereas in vivo KYN supplementation largely reversed Cur-mediated protection. Collectively, this study reveals a novel gut-liver axis in MASLD pathogenesis, demonstrating that Cur alleviates hepatic steatosis by targeting the microbiota-KYN-AHR-H3K27ac-Cebpb epigenetic axis, positioning Cur supplementation and KYN modulation as promising therapeutic strategies for MASLD intervention.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13675466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149208362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Colitis-associated colorectal carcinogenesis: molecular mechanisms and therapeutic potential.","authors":"Yi Lu, Xixi Wang, Cuike Yin, Jiaxuan Wang, Shaoqing Guo, Zihan Wang, Jing Zhou, Mengyuan Cui, Xiaoxia Cheng, Lei Zhang, Changjiang Qin","doi":"10.1186/s43556-026-00623-0","DOIUrl":"10.1186/s43556-026-00623-0","url":null,"abstract":"<p><p>Chronic colitis is a major risk factor for colorectal cancer (CRC), particularly for colitis-associated colorectal cancer (CAC), where persistent inflammation drives the transition from mucosal injury to malignant transformation. Accumulating evidence indicates that gut microbiota dysbiosis, epithelial barrier disruption, microbial translocation, chronic immune activation, and aberrant inflammatory signaling collectively contribute to CAC initiation and progression. Sustained inflammation promotes oxidative stress, DNA damage, genetic/epigenetic alterations, and tumor microenvironment remodeling, ultimately facilitating tumor development and immune evasion. These processes form an interconnected pathogenic network linking microbial, inflammatory, genetic, immune, and stromal alterations. This review comprehensively summarizes the key drivers and molecular mechanisms of CAC, covering microbiota and barrier dysfunction, inflammatory signaling, oxidative stress and DNA damage, genetic and epigenetic alterations, and tumor microenvironment remodeling and immune dysregulation. We further review recent advances in diagnostic biomarkers, disease monitoring, chemoprevention, targeted therapies, and emerging interventions, including the potential utility of specific chemokine axes as biomarkers and therapeutic targets. Particular emphasis is placed on the translational challenges of linking mechanistic insights to diagnostic and therapeutic advances, including biomarker validation, stage-specific interventions, and patient stratification across disease progression. By integrating these interconnected mechanisms and therapeutic strategies, this review provides a comprehensive framework for understanding CAC pathogenesis and identifies opportunities for precision prevention, early detection, and multimodal treatment.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672773/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198374","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Docosahexaenoic acid remodels lipid composition of lipid rafts and mitochondrial function in ApoE4/4 mouse brain: a multi-omic investigation.","authors":"Yu Liu, Jingjing Xu, Xixiang Wang, Lu Liu, Xiuwen Ren, Yunyun Gong, Chen Miao, Mengyang Sun, Shaobo Zhou, Xinjing Guo, Linhong Yuan","doi":"10.1186/s43556-026-00618-x","DOIUrl":"10.1186/s43556-026-00618-x","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is an irreversible neurodegenerative disorder lacking curative therapies, with ApoE4 as the strongest genetic risk factor driving lipid dyshomeostasis and neuronal damage in the central nervous system. Lipid rafts, cholesterol- and sphingolipid-rich membrane microdomains, govern key neuronal signalling, and dysfunction of these microdomains mediates the progression of preclinical pathological lesions in ApoE4 carriers. Dietary docosahexaenoic acid (DHA) is widely reported to mitigate brain lipid disorders, yet how DHA remodels subfractions of lipid raft and non-raft membrane domains to rescue ApoE4-related energy metabolism disorder remains unclear. Most existing studies have only quantified total brain lipids without distinguishing membrane subdomains, and few characterized the liver-brain metabolic axis underlying ApoE4-associated neurodegeneration. We constructed female ApoE3/3 and ApoE4/4 knock-in mice with 6- and 12-month DHA dietary interventions, combining behavioral, histological, lipidomic and proteomic assays to characterize genotype-specific lipid remodelling and downstream mitochondrial changes. Here we show that ApoE4 mice develop severe hepatic steatosis, neuroinflammation and lipid raft rigidification characterized by elevated sulfatides and ceramides levels, DHA upregulates Lpin1, Atgl and nSMase2 while suppressing Acer3 and Sgms2, thereby rebalancing lipids raft and restoring mitochondrial bioenergetics. Our work resolves raft and non-raft lipid profiles in ApoE humanized mice, and links peripheral hepatic metabolic disturbances to cerebral membrane microdomain dysfunction. These multi-omics mechanistic findings advance genotype-specific preventive nutritional strategies for ApoE4 carriers and reveal potential subcellular lipid targets for early AD intervention.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13672281/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149198281","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alistipes-derived monomethyl branched-chain fatty acid iso-15:0 suppresses hepatocellular carcinoma progression by inhibiting Gβγ/PI3K/AKT signaling.","authors":"Juan He, Yu Chen, Liwen Kuang, Yang Xiao, Jiongming Chen, Xudong Liu, Jiangang Zhang, Ziyi Li, Dongqin Zhou, Miaoyu Song, Yi Yi, Danyang Li, Haili Shang, Nan Zhang, Ran Ren, Yu Zhou, Juan Lei, Huakan Zhao, Yongsheng Li","doi":"10.1186/s43556-026-00622-1","DOIUrl":"10.1186/s43556-026-00622-1","url":null,"abstract":"<p><p>The role of gut microbiota and their metabolites in the progression of hepatocellular carcinoma (HCC) has garnered increasing attention. Although Alistipes, a genus frequently reported as a beneficial bacterium, has been associated with antitumor effects and enhanced efficacy of cancer therapies, its specific functions and underlying mechanisms in HCC remain poorly defined. In this study, 16S rDNA sequencing revealed a marked decrease in the abundance of Alistipes in fecal samples from HCC patients compared to healthy controls, a finding that was also observed in HCC mouse models. Additionally, iso-15:0, an important fatty acid metabolite derived from Alistipes, was found to be significantly reduced in the feces of both HCC patients and HCC mouse models. Functional experiments demonstrated that iso-15:0 effectively suppresses the proliferation and migration of HCC cells in vitro and in vivo. Mechanistically, iso-15:0 inhibits the activation of the PI3K/AKT signaling pathway by interfering with G protein-coupled receptor (GPCR) downstream signaling, specifically through the Gβγ subunits. To further explore the potential for the clinical application of iso-15:0, we have developed a biomimetic nanodelivery system (3R/RGD/M1@iso-15:0 LNP) that markedly improves the delivery efficiency and therapeutic efficacy of iso-15:0 in vivo. Our findings elucidate for the first time that iso-15:0, derived from Alistipes, suppresses HCC progression by restricting the Gβγ-PI3K/AKT signaling axis, highlighting its potential as a novel therapeutic strategy for HCC.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669273/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetically silencing gluconeogenic enzyme PCK1 by EZH2 promotes renal tubulointerstitial fibrosis.","authors":"Ming Wu, Pinglan Lin, Zhiqiang Yan, Yanzhe Wang, Anna Rinaldi, Pietro E Cippà, Di Huang, Jiayi Qiao, Aidong Yang, Bo Tan, Chaoyang Ye, Dongping Chen","doi":"10.1186/s43556-026-00617-y","DOIUrl":"10.1186/s43556-026-00617-y","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is a leading cause of global morbidity. The kidney is a major gluconeogenic organ, and impaired renal gluconeogenesis contributes to CKD, yet the regulatory mechanisms remain poorly understood. Here we show that enhancer of zeste homolog 2 (EZH2), a histone H3K27 trimethyltransferase, epigenetically suppresses renal gluconeogenesis and drives tubulointerstitial fibrosis. Through integrative multi-omics profiling (RNA-seq, CUT&Tag, and single-nucleus RNA-seq), we show that EZH2 directly binds to and deposits H3K27 trimethylation at promoters of gluconeogenic genes in proximal tubular cells, with the most prominent repression observed at phosphoenolpyruvate carboxykinase (Pck1) gene. In fibrotic kidneys, Ezh2 is markedly upregulated in proximal tubules and inversely correlates with Pck1 expression across injury and maladaptive repair states. Genetic ablation or pharmacological inhibition of EZH2 restores PCK1 expression, enhances lactate-to-glucose conversion, and attenuates extracellular matrix deposition and fibrotic marker expression in both cultured tubular cells and mouse models of kidney fibrosis. Stable isotope ¹³C-lactate tracing shows that tubular Ezh2 deletion increases the labelling fractions of gluconeogenic intermediates while reducing the labelling fraction of acetyl-CoA, indicating preferential partitioning of lactate-derived carbon towards gluconeogenesis rather than oxidative entry into the tricarboxylic acid (TCA) cycle in vivo. Mechanistically, Pck1 gain- and loss-of-function experiments establish PCK1 as a non-redundant downstream effector of EZH2's pro-fibrotic action. Collectively, our findings uncover an EZH2-PCK1 epigenetic-metabolic axis that couples histone methylation to gluconeogenic reprogramming and fibrogenesis. This axis may offer a dual therapeutic opportunity for CKD by concurrently restoring metabolic homeostasis and limiting fibrotic progression.</p>","PeriodicalId":74218,"journal":{"name":"Molecular biomedicine","volume":"7 1","pages":""},"PeriodicalIF":13.0,"publicationDate":"2026-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669293/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149186811","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}